Variant 7-102446865-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001126340.3(ORAI2):c.578G>A(p.Gly193Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ORAI2
NM_001126340.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.60

Variant links:

Genes affected

ORAI2 (HGNC:21667): (ORAI calcium release-activated calcium modulator 2) Predicted to enable store-operated calcium channel activity. Predicted to be involved in store-operated calcium entry. Predicted to be located in growth cone. Predicted to be integral component of membrane. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ORAI2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.906

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORAI2	NM_001126340.3 link	c.578G>A	p.Gly193Asp	missense_variant	Exon 4 of 4	ENST00000495936.7	NP_001119812.1	Q96SN7
ORAI2	NM_001271818.2 link	c.578G>A	p.Gly193Asp	missense_variant	Exon 4 of 4		NP_001258747.1	Q96SN7
ORAI2	NM_032831.4 link	c.578G>A	p.Gly193Asp	missense_variant	Exon 3 of 3		NP_116220.1	Q96SN7
ORAI2	NM_001271819.2 link	c.347G>A	p.Gly116Asp	missense_variant	Exon 3 of 3		NP_001258748.1	B4DUB4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ORAI2	ENST00000495936.7 link	c.578G>A	p.Gly193Asp	missense_variant	Exon 4 of 4	2	NM_001126340.3	ENSP00000420178.2		Q96SN7C9JQR7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461266

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726972

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.578G>A (p.G193D) alteration is located in exon 4 (coding exon 2) of the ORAI2 gene. This alteration results from a G to A substitution at nucleotide position 578, causing the glycine (G) at amino acid position 193 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.083

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;D;T;D;T;D;D

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.88

.;D;D;.;D;.;.

M_CAP

Benign

0.030

MetaRNN

Pathogenic

0.91

D;D;D;D;D;D;D

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.8

M;M;.;M;.;M;M

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.8

.;N;N;N;N;N;N

REVEL

Benign

0.26

Sift

Uncertain

0.0050

.;D;D;D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D;D;D;D

Polyphen

0.63

P;P;.;P;.;P;P

Vest4

0.76

MutPred

0.82

Gain of catalytic residue at G193 (P = 0.0901);Gain of catalytic residue at G193 (P = 0.0901);Gain of catalytic residue at G193 (P = 0.0901);Gain of catalytic residue at G193 (P = 0.0901);Gain of catalytic residue at G193 (P = 0.0901);Gain of catalytic residue at G193 (P = 0.0901);Gain of catalytic residue at G193 (P = 0.0901);

MVP

0.66

MPC

2.1

ClinPred

0.94

GERP RS

5.5

Varity_R

0.27

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over